A phase I/II study of the CXCR2 inhibitor, AZD5069, in combination with durvalumab, in patients (pts) with advanced hepatocellular carcinoma (HCC).
Authors: T.R. Jeffry Evans, Bristi Basu, Richard Hubner, Yuk Ting Ma, Tim Meyer, Daniel H. Palmer, David J. James Pinato, Elizabeth Ruth Plummer, Paul J. Ross, Adel Samson, Debashis Sarker, Timothy Kendall, Christopher Bellamy, Helen L Reeves, Fiona Thomson, Claire A Lawless, Jamie Stobo, Owen J Sansom, Derek A. Mann, Thomas G Bird
Journal: Journal of Clinical Oncology (2023)

TPS631 Background: HCC is increasing rapidly in incidence worldwide driven by a rise in chronic liver disease including non-alcoholic steato-hepatitis (NASH). Most pts are not suitable for curative or loco-regional treatments and may be candidates for systemic therapies. Immune checkpoint inhibitors combined with VEGF inhibition is a standard of care in HCC. However, a meta-analysis of 3 phase III randomised trials of PD-1 or PDL-1 inhibitors (n &gt; 1,600 pts) with HCC suggests that pts with NASH-related HCC treated with PD-1/PDL-1 inhibitors had reduced overall survival compared with other aetiologies. Neutrophils expressing the chemokine receptor CXCR2, crucial to neutrophil recruitment in acute-injury, are highly represented in NASH-HCC. In NASH-HCC murine models, lacking response to immune-checkpoint inhibitors, AZD5069 (CXCR2 inhibitor) in combination with anti-PDL-1 suppressed tumor burden and extended survival, accompanied by an increase in tumor-associated neutrophils which switched from a pro-tumor to anti-tumor progenitor-like neutrophil phenotype. We propose that inhibition of CXCR2 may potentiate the efficacy of anti-PDL-1 inhibition in pts with HCC. Methods: In this multi-centre (n = 10) study, pts with biopsy-confirmed HCC, PS ECOG &lt; 1, Child-Pugh A, &lt; 1 prior systemic therapies, receive 1 of escalating doses of AZD5069 (bid, po daily) with Durvalumab (1.5 gm iv on day 1) in 28-day cycles for up to 2 years to determine the recommended phase II dose using a Keyboard design, followed by an additional cohort of pts to determine the anti-tumor efficacy of this combination using a Simon’s two-stage design (min 18, max 35 pts; target objective response rate &gt; 30%; unacceptable response rate &lt; 10%). Dose limiting toxicities (DLTs) are assessed during cycle 1. Disease assessments are performed 8-weekly (12-weekly after 1 year). The 1st dose cohort has been completed with no DLTs. The 2 nd dose cohort opened to recruitment in September 2022. Exploratory studies (blood; pre- &amp; on-treatment tumor and non-malignant liver biopsies) include biomarkers of CXCR2 inhibition (blood); proof-of-mechanism (tumor: expression of CXCR2, PD-L1, PD-1, CD8, CD4, CD66b, CD69); proof-of-mechanism (blood: ctDNA); drug-induced changes of mRNA expression, CXCR2 ligands &amp; signalling pathway genes, T-cell and myeloid cell pathways, neutrophil-associated genes; predictive biomarkers (blood and tumour) include biomarkers of the CXCR2/PD-L1 immune axis; aberrant CXCR2 signalling pathways; proliferation biomarkers and CD10 (neutrophils), CD68 (macrophages), CD103 (T-regs); tumour mutational status. This study is funded by a grant from Cancer Research UK (A29287) and is co-sponsored by University of Glasgow and NHS Greater Glasgow &amp; Clyde. Study sites are supported by the Experimental Cancer Medicine Centre Network. AZD5069 and Durvalumab are provided by Astra Zeneca. Clinical trial information: 2020-003346-36 .